text: Ligands of the TRPV1 receptor seem to act from the intracellular side. This is an unusual property of TRPV1, where ligands of most other ligand-gated channels bind from the extracellular space. Capsaicin is highly lipophilic and can pass the plasma membrane easily. It is generally accepted that capsaicin acts on and binds to the TRPV1 receptor from the intracellular side prior to activation. The critical sites for capsaicin binding are Arg 114 and Glu 761 at the N- and C-termini of the receptor, respectively. Because these two amino acids are charged and located in the cytosolic part of TRPV1 receptor, the two regions are likely to be implicated in hydrophilic interaction of TRPV1 with vanilloids such as capsaicin and RTX.
  In addition to these sites in N- and C-termini of TRPV1, a region in the intracellular linker sited in the transmembrane domain, called the TM3 region, has been shown to be critical for hydrophobic interaction with vanilloids. The TM3 region is considered to be necessary for binding to vanilloids. It is surrounded by the hydrophobic environment because of its placement in the plasma membrane. Now it is recognized as an important link in hydrophobic interaction with capsaicin. The binding sites Arg 114 and Glu 761 and the TM3 region in TRPV1, together consist of a binding pocket to vanilloids.